PROJECT SUMMARY/ABSTRACT - Project 1 Project 1 will investigate the underlying mechanisms and test the benefits of integrating stone-specific (S- mode) ultrasound (US) imaging, burst wave lithotripsy (BWL), and ultrasonic propulsion (UP) and of acoustic tractor beams to image, comminute, and expel urinary stones. Urinary stone disease is the costliest non- malignant urologic disease. The ability to non-invasively break stones and expel the fragments in an office or clinic setting has the potential to reduce risk, reduce cost, and improve care. This Project seeks to answer the major scientific hurdles to this revolutionary vision: find the stone, break the stone, and expel the stone. In Aim 1, Project 1 with Project 3 will conduct the first-in-human test of BWL. We will observe by ureteroscopy the fragmentation of humans stones in vivo. To the first test of BWL alone, we will compare the comminution effectiveness and safety of BWL employed where the output is adapted in response to feedback. At a minimum, in the feedback-based, adaptive control group, UP will be interleaved with BWL, which in preliminary preclinical studies accelerated stone comminution threefold, and also enabled visual feedback on treatment endpoint by dispersing clusters of fragments that otherwise appeared as an intact stone. In Aim 2, we will conduct a randomized controlled trial of the benefits and risks of fragmenting and expelling stones in a urology clinic. We will compare no intervention to expulsion by combined application of BWL and UP to remove stones. Stones will be targeted by S-mode imaging, broken by BWL, and expelled by UP to facilitate natural clearance from the urinary tract. Stone burden, adverse events, and Quality of Life (QOL) will be measured by imaging, telephone and chart reviews, and the Wisconsin Stone QOL questionnaire, respectively. It is important to locate and target small stones not always seen on standard imaging. We have observed that even low amplitude UP or BWL pulses have a synergistic effect with Doppler US stone detection resulting in increased contrast of the stone against the background image. In Aim 3, we will add low frequency pulses from the UP probe in concert with the S-mode pulses and measure the improvement of signal to clutter ratio in the images. Three-dimensional (3D) S-mode imaging will be generated by rotating the imaging probe within the therapy probe. A blinded study to localize small stones implanted in a pig (n=20) will be conducted to measure sensitivity, specificity, and user variability with and without the low frequency enhancement. Lastly in Aim 4 we address how to expel fragments from tight spaces. We will develop and validate in vivo a remote tractor beam to grasp and carry fragments through the complex 3D path of the urinary space and out of the kidney. We will a) visualize with 3D US imaging the path, b) create beams to move the stone, and c) trap and attempt to expel stones from the kidneys of pigs (n=20). We will compare calculations and measurements of the forces for a range of acoustic intensities, beams, and stone sizes, numbers, shapes, and compositions.